Title: Lipase-Colipase Inhibitor (H0506B)
Inventor: Charlotte Erlanson-Albertsson
Background of the invention
Lipases is a group of enzymes taking part in the digestion of fat by hydrolysing lipids present in the food thereby allowing absorption of the fat by the intestinal tract. The lipases are mainly three, viz gastric lipase, pancreatic lipase and carboxylic ester lipase.
Pancreatic lipase is the main enzyme responsible for the hydrolysis of triacylglycerols in the diet. The pancreatic lipase is a typical lipase catalysing the hydrolysis of water-insoluble substrates forming an interface. The enzyme is said to be activated by interfaces.
The most peculiar property of pancreatic lipase is that its activity is strongly inhibited by surface active agents like the naturally occurring bile salts. To overcome this, Nature has come to use another pancreatic protein, colipase.
Colipase binds to lipase in a 1:1 molar ratio and also binds to the bile-salt covered triacylglycerol interface in this way anchoring lipase to its triacylglycerol substrate. Colipase as such has no lipolytic activity.
Obesity has in recent days become an ever-increasing problem to population of the industrialized world, whereby e.g., the average weight of a male at the age of 20 has increased about 10 kilogrammes during the last 20 years. Obesity leads to the formation of the so-called metabolic syndrome, to which diabetes and cardio-vascular diseases belong. The worst forms of obesity are visceral fat accumulation, liver fat accumulation and even muscular fat accumulation.
The high fat intake is due to a number of factors, such as sitting still, fat rich food (so called “junk food”), and erroneous diet information. It is also a relic of old days tradition of having a large calorie intake based on a heavy workday.
Food of today does not provide for a long-term feeling of satisfaction either, which in turn leads to an increased food intake. However, a lipid diet remaining in the intestine will increase the feeling of satisfaction for a longer time period.
The present compounds have been tested in different models, in vitro and in vivo, with excellent results.
In vitro
Determination of lipolysis by colipase/lipaseThe inhibiting effect in the in vitro model used of different compounds of the invention is given in Table 1 below.
Table 1
Amount of inhibitor
(_mol)
Activity Control
(_mol/min)Activity Inhibitor
(_mol/min)0
12.44 Inhibitor I
0.356
0.069
6.81 Inhibitor II
0.319
0.069
7.85 Inhibitor III
0.312
0.04
8.04 Inhibitor IV
0.244
0.033
7.25 Inhibitor V
0.257
0.045
In vivo
MethodSprague-Dawley rats were fed 1 ml of Intralipid (200 mg/ml) with and without inhibitor. Blood samples were taken at time 0, prior to the test start, and then after 30, 60, 120 and 180 minutes, respectively, after feeding with Intralipid. Analyses of free fatty acids, and triglycerides were made.
Table 2
In vivo experiments in accordance with the in vivo protocol
Inhibitor
Free fatty acids
(mmol)Triglycerides
(mg/dl)
0
30
60
120
180
0
30
60
120
180
Control
0.60
0.92
1.05
0.95
0.85
96
111
109
130
95
Compound Inhibitor II
0.56
0.63
0.70
0.60
0.62
103
95
98
95
77
Table 3
Compound Inhibitor II in a dose-response evaluation
Dose of active active compound
(_g)
Free fatty acids
(mmol)Free fatty acids
(% of control)0
1.45
100
10
1.25
83.7
50
0.83
56.1
100
0.85
57.4
The conclusion is that the inhibitors of the present invention have effects both in in vitro as well as in in vivo systems, which can be expected to provide for a great potential at the treatment of high blood lipid levels, diabetes type 2 and obesity.
Forskarpatent I Syd AB hereby offers any interested party to acquire a right to this invention under terms to be agreed upon.
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